Journal of Alzheimer's Disease - Volume 56, issue 1

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ISSN 1387-2877 (P)

ISSN 1875-8908 (E)

Impact Factor 2018: 3.476

The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.

The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.

Abstract: We previously reported that neuroinflammation contributes to the amnesia of AβPPswe/PSEN1dE9 Alzheimer’s disease model mice fed a high-fat diet to induce type-2 diabetes (T2DM-AD mice), but the underlying mechanism for the memory decline remained unclear. Recent studies have suggested that cholinergic modulation is involved in neuroinflammatory cellular reactions including neurogenesis and gliosis, and in memory improvement. In this study, we administered a broad-spectrum cholinesterase inhibitor, rivastigmine (2 mg/kg/day, s.c.), into T2DM-AD mice for 6 weeks, and evaluated their memory performance, neurogenesis, and neuroinflammatory reactions. By two hippocampal-dependent memory tests, the Morris water maze and contextual fear conditioning, rivastigmine improved the memory…deterioration of the T2DM-AD mice (n = 8, p < 0.01). The number of newborn neurons in the hippocampal dentate gyrus was 1138±324 (Ave±SEM) in wild-type littermates, 2573±442 in T2DM-AD-Vehicle, and 2165±300 in T2DM-AD-Rivastigmine mice, indicating that neurogenesis was accelerated in the two T2DM-AD groups (n = 5, p < 0.05). The dendritic maturation of new neurons in T2DM-AD-Vehicle mice was severely abrogated, and rivastigmine treatment reversed this retarded maturation. In addition, the hippocampus of T2DM-AD-Vehicle mice showed increased proinflammatory cytokines IL-1β and TNF-α and gliosis, and rivastigmine treatment blocked these inflammatory reactions. Rivastigmine did not change the insulin abnormality or amyloid pathology in these mice. Thus, cholinergic modulation by rivastigmine treatment led to enhanced neurogenesis and the suppression of gliosis, which together ameliorated the memory decline in T2DM-AD model mice.
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Abstract: Plasma biomarkers to aid the early diagnosis of Alzheimer’s disease (AD) or to monitor disease progression have long been sought and continue to be widely studied. Biomarkers that correlate with AD polygenic risk score, a measure of the polygenic architecture of the disease and highly predictive of AD status, would be excellent candidates. Therefore, we undertook a preliminary study to assess the association of plasma inflammatory biomarkers with an overall AD polygenic risk score as well as with an inflammation-specific AD polygenic risk score in a sample set of 93 AD cases. We measured five complement biomarkers [complement receptor 1…(CR1), clusterin, complement component 9 (C9), C1 inhibitor (C1inh), terminal complement complex (TCC)] and the benchmark inflammatory marker C-reactive protein (CRP). Plasma clusterin level showed an association with overall AD polygenic risk score, while clusterin, C1inh, and CRP levels each displayed some association with the inflammatory-specific AD polygenic risk score. The results suggest that elevated plasma levels of inflammatory biomarkers, including complement proteins, associate with polygenic risk scores in AD, further strengthening the link between genetic and biomarker disease predictors and indicating a potential role for these markers in disease prediction and patient stratification in AD.
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Abstract: Background: Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer’s disease (AD). Objective: We aimed at reporting APP mutations associated with CAA, describe the clinical, cerebrospinal fluid AD biomarkers, and neuroimaging features, and compare them with the data from the literature. Methods: We performed a retrospective study in two French genetics laboratories by gathering all clinical and neuroimaging data from patients referred for a genetic diagnosis of CAA with an age of onset before 66 years and fulfilling the other Boston revised criteria. We studied the segregation of mutations in families and…performed a comprehensive literature review of all cases reported with the same APP mutation. Results: We screened APP in 61 unrelated French patients. Three mutations, located in the Aβ coding region, were detected in five patients from three families: p.Ala692Gly (Flemish), p.Glu693Lys (Italian), and p.Asp694Asn (Iowa). Patients exhibited CAA and progressive cognitive impairment associated with cortical calcifications in the Iowa and Italian mutation carriers, but not the patient carrying the Flemish mutation. Conclusions: This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature.
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Abstract: Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer’s disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate…receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD.
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Abstract: Background: The major genetic risk factor for late onset Alzheimer’s disease (AD) is the APOE -ɛ 4 allele. However, APOE -ɛ 4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. Objective: To identify genetic factors that, next to APOE -ɛ 4 homozygosity, contribute to the development of AD. Methods: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1 , PSEN2 , or APP . We collected DNA from four affected and seven unaffected family members and…performed exome sequencing on DNA from three affected and one unaffected family members. Results: All affected family members were homozygous for the APOE -ɛ 4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE -ɛ 4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. Conclusion: We hypothesize that next to APOE -ɛ 4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.
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Abstract: Background: Little is known about the sample sizes required for clinical trials of Alzheimer’s disease (AD)-modifying treatments using atrophy measures from serial brain magnetic resonance imaging (MRI) in the Japanese population. Objective: The primary objective of the present study was to estimate how large a sample size would be needed for future clinical trials for AD-modifying treatments in Japan using atrophy measures of the brain as a surrogate biomarker. Methods: Sample sizes were estimated from the rates of change of the whole brain and hippocampus by the k-means normalized boundary shift integral (KN-BSI) and cognitive…measures using the data of 537 Japanese Alzheimer’s Neuroimaging Initiative (J-ADNI) participants with a linear mixed-effects model. We also examined the potential use of ApoE status as a trial enrichment strategy. Results: The hippocampal atrophy rate required smaller sample sizes than cognitive measures of AD and mild cognitive impairment (MCI). Inclusion of ApoE status reduced sample sizes for AD and MCI patients in the atrophy measures. Conclusion: These results show the potential use of longitudinal hippocampal atrophy measurement using automated image analysis as a progression biomarker and ApoE status as a trial enrichment strategy in a clinical trial of AD-modifying treatment in Japanese people.
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Abstract: We recently introduced model-based “physiomarkers” of dynamic cerebral autoregulation and CO2 vasomotor reactivity as an aid for diagnosis of early-stage Alzheimer’s disease (AD) [1 ], where significant impairment of dynamic vasomotor reactivity (DVR) was observed in early-stage AD patients relative to age-matched controls. Milder impairment of DVR was shown in patients with amnestic mild cognitive impairment (MCI) using the same approach in a subsequent study [2 ]. The advocated approach utilizes subject-specific data-based models of cerebral hemodynamics to quantify the dynamic effects of resting-state changes in arterial blood pressure and end-tidal CO2 (the putative inputs) upon cerebral blood flow velocity…(the putative output) measured at the middle cerebral artery via transcranial Doppler (TCD). The obtained input-output models are then used to compute model-based indices of DCA and DVR from model-predicted responses to an input pressure pulse or an input CO2 pulse, respectively. In this paper, we compare these model-based indices of DVR and DCA in 46 amnestic MCI patients, relative to 20 age-matched controls, using TCD measurements with their counterparts using Near-Infrared Spectroscopy (NIRS) measurements of blood oxygenation at the lateral prefrontal cortex in 43 patients and 22 age-matched controls. The goal of the study is to assess whether NIRS measurements can be used instead of TCD measurements to obtain model-based physiomarkers with comparable diagnostic utility. The results corroborate this view in terms of the ability of either output to yield model-based physiomarkers that can differentiate the group of aMCI patients from age-matched healthy controls.
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Abstract: We aimed to analyze the risk of non-cancer mortality according to duration of antipsychotic use and to compare the risk associated with polypharmacy and monotherapy among community-dwellers with Alzheimer’s disease (AD). The risk of mortality between most frequently used antipsychotic drugs was compared. Data from a nationwide register-based MEDALZ study that included all 70,718 community-dwellers newly diagnosed with AD during 2005–2011 in Finland was utilized. Death, excluding cancer as direct cause of death, was extracted from Causes of Death Register. Incident antipsychotic use was compared with time without antipsychotics with Cox proportional hazard models. Antipsychotic use was associated with an…increased risk of mortality (adjusted hazard ratio [aHR] 1.61; 95% Confidence Interval [CI] 1.53–1.70). The absolute difference in mortality rate was 4.58 (95% CI 4.53–4.63) deaths per 100 person-years. The risk of mortality was increased from the first days of use and attenuated gradually but remained increased even after two years of use (aHR 1.30; 95% CI 1.16–1.46). Compared with nonuse, antipsychotic polypharmacy (aHR 2.88; 95% CI 2.38–3.49) was associated with an increased risk of mortality than monotherapy (aHR 1.57; 95% CI 1.49–1.66). Haloperidol was associated with higher risk of mortality (aHR 1.52; 95% CI 1.14–2.02) and quetiapine with lower risk (aHR 0.84; 95% CI 0.75–0.94) compared with risperidone. In conclusion, the findings support current treatment guidelines on having a high threshold for antipsychotic initiation among persons with AD. Antipsychotic polypharmacy and long-term use should be avoided and drug choice should be weighed against risk/benefit evidence.
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Abstract: Background: Risk of pneumonia is increased in persons with Alzheimer’s disease (AD). In some studies, anticholinergic drugs (AC) have been associated with an increased pneumonia risk. Objective: We analyzed the risk of pneumonia associated with ACs in persons with AD. Methods: We performed a nested case-control study using register-based data from a Finnish nationwide MEDALZ cohort including all community-dwelling persons diagnosed with AD during 2005–2011. Cases were identified based on pneumonia diagnoses (n = 12,442) from hospital discharge and causes of death registers. Up to two controls without pneumonia were matched based on time since AD…diagnoses, age, and gender for each case; AC use was measured using Anticholinergic Drug Scale. Results: Use of AC was associated with an increased risk of pneumonia (adjusted odds ratio (OR) 1.36, 95% confidence interval (CI) 1.29–1.43). However, there was no increased pneumonia risk in persons using level 3 ACs. Incident use was associated with higher risk of pneumonia (OR 2.68, 95% CI 2.15–3.34) than prevalent use (OR 1.48, 95% CI 1.40–1.57). Among persons using cholinesterase inhibitors (AChEIs), risk of pneumonia was increased in persons using also ACs (OR 1.53, 95% CI 1.41–1.66). Conclusion: ACs were associated with an increased risk of pneumonia in persons with AD, especially at the time of initiation of these drugs. AC use was associated with increased pneumonia risk also in persons using AChEIs. This risk should be carefully considered when treating AD patients.
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